Novel compounds

ABSTRACT

The invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.

FIELD OF THE INVENTION

[0001] The present invention provides new triazolo[4,5-d]pyrimidinecompounds, their use as medicaments, compositions containing them andprocesses for their preparation.

BACKGROUND OF THE INVENTION

[0002] Platelet adhesion and aggregation are initiating events inarterial thrombosis. Although the process of platelet adhesion to thesub-endothelial surface may have an important role to play in the repairof damaged vessel walls, the platelet aggregation that this initiatescan precipitate acute thrombotic occlusion of vital vascular beds,leading to events with high morbidity such as myocardial infarction andunstable angina. The success of interventions used to prevent oralleviate these conditions, such as thrombolysis and angioplasty is alsocompromised by platelet mediated occlusion or re-occlusion.

[0003] A number of converging pathways lead to platelet aggregation.Whatever the initial stimulus, the final common event is a cross-linkingof platelets by binding of fibrinogen to a membrane-binding site,glycoprotein Ub/IIIa (GPIIb/IIIa). The high anti-platelet efficacy ofantibodies or antagonists for GPIIb/IIIa is explained by theirinterference with this final common event. However, this efficacy mayalso explain the bleeding problems that have been observed with thisclass of agent. Thrombin can produce platelet aggregation largelyindependently of other pathways but substantial quantities of thrombinare unlikely to be present without prior activation of platelets byother mechanisms. Thrombin inhibitors such as hirudin are highlyeffective anti-thrombotic agents, but again may produce excessivebleeding because they function as both anti-platelet and anti-coagulantagents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630;The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)IIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L.et. al. (1994) Circulation 90, pp. 1638-1642).

[0004] It has been found that adenosine 5′-diphosphate (ADP) acts as akey mediator of thrombosis. A pivotal role for ADP is supported by thefact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT,serotonin) will only produce a-gregation in the presence of ADP. Thelimited anti-thrombotic efficacy of aspirin may reflect the fact that itblocks only one source of ADP which is that released in athromboxane-dependent manner following platelet adhesion (see e.g.Antiplatelet Trialists' Collaboration (1994), Br. Mecl. J. 308, pp.81-106 and Antiplatelet Trialists' Collaboration (1994), Br. Med. J.308, pp. 159-168). Aspirin has no effect on aggregation produced byother sources of ADP, such as damaged cells or ADP released underconditions of turbulent blood flow.

[0005] ADP-induced platelet aggregation is mediated by the P_(2T)receptor subtype located on the platelet membrane. The P_(2T) receptor(also known as P2Y_(ADP) or P2T_(AC)) is primarily involved in mediatingplatelet aggregation/activation and is a G-protein coupled receptorwhich is as yet uncloned. The pharmacological characteristics of thisreceptor have been described, for example, in the references byHumphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Faguraet al., Br. J. Pharmacology (1998) 124, 157-164. Recently it has beenshown that antagonists at this receptor offer significant improvementsover other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213).Accordingly there is a need to find further P_(2T) (P2Y_(ADP) orP2T_(AC)) antagonists as anti-thrombotic agents.

[0006] International Patent Application WO 9905143 discloses genericallya series of triazolo[4,5-d]pyrimidine compounds having activity asP_(2T) (P²Y_(ADP) or P2T_(AC)) antagonists. It has now been found thatcertain compounds within the scope of International Patent ApplicationWO 9905143 but not specifically disclosed therein exhibit high potencycombined with surprisingly high metabolic stability and bioavailibility,such that the predicted therapeutic dose for prolonged inhibition ofaggregation in man shows advantage.

DESCRIPTION OF THE INVENTION

[0007] In a first aspect the invention therefore provides a compound offormula (I):

[0008] wherein:

[0009] R¹ is C₃₋₅ alkyl optionally substituted by one or more halogenatoms;

[0010] R² is a phenyl group, optionally substituted by one or morefluorine atoms;

[0011] R³ and R⁴ are both hydroxy;

[0012] R is XOH, where X is CH₂, OCH₂CH₂ or a bond;

[0013] or a pharmaceutically acceptable salt or solvate thereof, or asolvate of such a salt.

[0014] provided that:

[0015] when X is CH₂ or a bond, R¹ is not propyl.

[0016] when X is CH₂ and R¹ is CH₂CH₂CF₃, butyl or pentyl, the phenylgroup at R² must be substituted by fluorine.

[0017] when X is OCH₂CH₂ and R¹ is propyl, the phenyl group at R² mustbe substituted by fluorine.

[0018] Alkyl groups, whether alone or as part of another group arestraight chained and fully saturated.

[0019] Suitably R¹ is a C₃₋₅ alkyl optionally substituted by one or morefluorine atoms. Preferably R¹ is C₃₋₅ alkyl optionally substituted onthe terminal carbon by three fluorine atoms. More preferably R¹ is3,3,3,-trifluoropropyl, butyl or propyl.

[0020] Suitably R² is phenyl or phenyl substituted by one or morefluorine atoms. Preferably R² is phenyl, 4-fluorophenyl or3,4-difluorophenyl.

[0021] Suitably R is XOH where X is CH₂, OCH₂CH₂ or a bond.

[0022] Preferably R is CH₂OH or OCH₂CH₂OH.

[0023] Particularly preferred compounds include:

[0024][1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropylamino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[0025][1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[0026][1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;

[0027][1R-[1α,2α,3β(1R*,2*),5β]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;

[0028][1S-[1α,2α,3β,4α(1S*,2R*)]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;

[0029][1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;

[0030][1S-[1α,2α3β5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol

[0031][1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;

[0032][1S-[1α,2α,3β(1S*,2R*),5]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol;

[0033] and pharmaceutically acceptable salts or solvates thereof, orsolvates of such salts.

[0034] According to the invention there is further provided a processfor the preparation of a compound of formula (I) which comprises:

[0035] (a) reacting a compound of formula (II):

[0036] where R, R¹, R³ and R⁴ are as defined in formula (I), or areprotected derivatives thereof, or R³ and R⁴ together form a bond in the5-membered ring, or R is CH₂CH₂OR′, where R′ is C₁₋₆ alkyl or benzyl,and L is a leaving group such as halogen or SR, with a compound offormula (I):

[0037] where R² is as defined in formula (I), or is a protectedderivative thereof,

[0038] or where X is a bond:

[0039] (b) hydroxylation of a compound of formula (IV):

[0040] where R¹ is defined in formula (I) and R⁸ is H or CH₂CH₂OP³ whereP³ is H or a protecting group or R⁸ is CH₂COOR′ where R′ is C₁₋₆ alkylor benzyl, and Z is NH₂ or

[0041] where R2 is defined in formula (I).

[0042] and for both (a) and (b) optionally thereafter and in any order:

[0043] converting one or more functional groups into further functionalgroups;

[0044] removing any protecting groups;

[0045] forming a pharmaceutically acceptable salt or solvate, or asolvate of such a salt.

[0046] Compounds of formula (II) can be reacted with amines of formula(III) in the presence of a base, such as a tertiary organic amine, in aninert solvent, such as dichloromethane, at ambient or elevatedtemperature. Other suitable bases include inorganic bases such aspotassium carbonate.

[0047] The hydroxy groups R³ and R⁴ can be protected as groups OP¹ andOP² where P¹ and P² are protecting groups. Examples of suitableprotecting groups in compounds of formula (II) are C₁₋₆ alkyl(preferably methyl), benzyl, (C₁₋₆alkyl)₃Si (preferablyt-butyldimethylsilyl), and a C(O)C₁₋₆alkyl group such as acetyl.Preferably the two groups P¹ and P² together with the atoms to whichthey are attached form an alkylidene ring such as a methylidene orisopropylidene ring. Alternatively P¹ and P² can form analkoxymethylidene ring such as ethoxymethylidene.

[0048] Protecting groups can be added and removed using known reactionconditions. The use of protecting groups is fully described in‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, PlenumPress (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition,T W Greene & P G M Wutz, Wiley-Interscience (1991).

[0049] Ester protecting groups can be removed by basic hydrolysis, forexample by using a metal hydroxide, preferably an alkali metalhydroxide, such as sodium hydroxide or lithium hydroxide, or quaternaryammonium hydroxide in a solvent, such as aqueous ethanol or aqueoustetrahydrofuran, at a temperature of from 10° to 100° C., preferably thetemperature is around room temperature, or by acidic hydrolysis using amineral acid such as HCl or a strong organic acid such astrichloroacetic acid in a solvent such as aqueous 1,4-dioxane.Trialkylsilyl protecting groups can be removed by the use of, forexample, a fluoride ion source, for example tetra-n-butylammoniumfluoride or hydrogen fluoride. When one or both of P¹ and P² are C₁₋₆alkyl, deprotection can be achieved using boron tribromide. Benzylgroups can be removed by hydrogenolysis using a transition metalcatalyst, for example palladium on charcoal, under an atmosphere ofhydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as aceticacid.

[0050] A compound of formula (II) can be prepared by diazotising acompound of formula (V):

[0051] wherein R¹ is as defined in formula (I), and R is as defined informula (I), or is a protected derivative thereof, or is OCH₂CO₂R′,where R′ is C₁₋₆ alkyl or benzyl, and L is as defined above and R³ andR⁴ are as defined in formula (I) or are protected derivatives thereof orR³ and R⁴ together form a bond in the 5-membered ring,

[0052] with a metal nitrite, for example an alkali metal nitrite,especially sodium nitrite in dilute aqueous acid, for example 2M HCl, orwith a C₁₋₆-alkyl nitrite, in an inert solvent, at a temperature of fromabout −20 to about 100° C. Preferred conditions are isoamyl nitrite inacetonitrile at about 80° C.

[0053] A compound of formula (V) wherein R is CH₂OH, R³ and R⁴ arehydroxyl or protected derivatives thereof and L is as defined above, canbe prepared by reducing a compound of formula (VI):

[0054] wherein R¹, L, P¹ and P² are as defined above.

[0055] The reduction of the nitro group can be carried out for exampleby using hydrogenation with a transition metal catalyst at a temperaturearound room temperature, for example palladium on charcoal under anatmosphere of hydrogen, preferably at a pressure from 1 to 5atmospheres, in a solvent, for example ethanol, or by using iron in anacidic solvent such as acetic acid at a temperature of about 100° C.

[0056] Reduction of the lactam can be carried out using complex metalhydrides such as lithium aluminium hydride in a solvent such as ether orpreferably, by using sodium borohydride in a suitable solvent such asmethanol.

[0057] A compound of formula (VI) can be prepared by reacting a compoundof formula (VII):

[0058] wherein L and R¹ are as defined above and L¹ is a leaving group,for example a halogen atom, wherein L and L¹ are preferably the same,with a compound of formula (VIII):

[0059] wherein P¹ and P² are as defined above, in the presence of a basesuch as C₁₋₆-alkyl-M or MH wherein M is a metal ion, for example n-butyllithium, in an inert solvent, such as tetrahydrofuran, at a temperatureof from about −10 to about 100° C. Preferably sodium hydride is used intetrahydrofuran at room temperature.

[0060] One or more functional groups can be converted into furtherfunctional groups using standard chemistry. A compound where X is a bondcan be converted to a compound where X is O(CH₂)₂ by treatment with basefollowed by LY where L is a leaving group and Y is (CH₂)₂OH or aprotected version thereof or Y is CH₂COOR′ where R′ is C₁₋₆ alkyl orbenzyl. A compound where R is CH₂CH₂OR may be converted into a compoundwhere R is O(CH₂)₂OH by reduction, for example using DIBAL-H®. The groupSR¹ can be interconverted by oxidation of the sulfur, for example usingoxone™ or mCBPA, followed by treatment with a compound R^(1′)-SM whereR^(1′) is a different R¹ group and M is a metal such as sodium.Alternatively the product of the sulfur oxidation may be treated withMSH where M is a metal such as sodium, followed by treatment with a baseand R^(1′)X where R^(1′) is a different R¹ group and X is a leavinggroup. Suitable bases include N,N-diisopropylethylamine.

[0061] A compound of formula (II) where R, R¹, R³, and R-are as definedin formula (I) or are protected derivatives thereof, or R³ and R⁴together form a bond in the 5-membered ring or R is OCH₂CO₂R where R isC₁₋₆ alkyl or benzyl, and L is a leaving group such as halogen, may beconverted into a compound of formula (II) where R, R¹, R³, and R⁴ aredefined above and L is NH₂ by treatment with a diazotizing agent in thepresence of a halogenating agent, preferably isoamyl-nitrite and carbontetrabromide.

[0062] A compound of formula (II) where R, R¹, R³, and R⁴ are definedabove and L is NH₂ may be prepared by treating a compound of formula(II) where R, R¹, R³, and R⁴ are as defined above and L is a leavinggroup such as halogen, with ammonia in a solvent such as methanol.

[0063] Compounds of formula (V) can also be prepared by treating acompound of formula (XI) R _ONH 2

[0064] where R, R³ and R⁴ are as defined in formula (I) or are protectedderivatives thereof or R is OCH₂CO₂R where R is C₁₋₆ alkyl or benzyl, orR³ and R⁴ together form a bond in the 5-membered ring,

[0065] with a compound of formula (VII) as defined above, followed byreduction of the nitro group. The reaction is carried out in an inertsolvent such as dichloromethane or 1,4-dioxane, in the presence of anon-nucleophilic base, such as N,N-diisopropylamine, at a tempeature ofabout −20° C. to about 150° C., preferably at ambient temperature.

[0066] Compounds of formula (II) where R is as defined in formula (I),R³ and R⁴ together form a bond in the 5-membered ring, and L is SR¹, ora protected derivative thereof, can be prepared by reacting a compoundof formula (XII):

[0067] where R¹ groups are as defined in formula (I),

[0068] with a compound of formula (XIII):

[0069] in which R⁷ is H or a protected derivative thereof. The reactioncan be carried out in the presence of a suitable transition metalcomplex, preferably tetrakistriphenylphosphine palladium(0).

[0070] Compounds of formula (XII) can be prepared from compounds offormula (XIV):

[0071] by reacting with a compound R¹X where R¹ is as defined in formula(I) and X is a leaving group such as halo, followed by cyclisation.

[0072] Compounds of formula (XI) where R is OH or a protected versionthereof and R³ and R⁴ are as defined in formula (I) or are protectedderivatives thereof may be prepared from compounds of formula (XIII)where R⁷ is H or a protecting group by treatment with a bisester ofimidodicarbamic acid using palladium catalysis followed by hydroxylationof the double bond, and optionally, deprotection of the nitrogen.Preferably imidodicarbonic acid, bis-(1,1-dimethylethyl)ester andtetrakistriphenylphosphine palladium(0) are used followed by osmiumtetroxide and deprotection using hydrochloric acid in methanol.

[0073] Compounds of formula (XI), where R is OCH₂CO₂R′ where R′ is C₁₋₆alkyl and R³ and R⁴ together form a bond in the 5-membered ring, may beformed from compounds of formula (XIII), where R⁷ is H or a protectinggroup, by treatment with an azide in the presence of a palladiumcatalyst, followed by reduction of the azide and alkylation of thealcohol as described previously.

[0074] Compounds of formula (XI) where R is OCH₂CH₂OH and R³ and R⁴ areas defined in formula (I) or are protected derivatives thereof may beprepared from compounds of formula (XI) where R is OH and R³ and R⁴ areas defined in formula (I) or are protected derivatives thereof, byprotection of the nitrogen, alkylation of the alcohol using a2-halo-acetic acid ester, followed by reduction of the ester anddeprotection of the nitrogen. We prefer protection of the nitrogen as acarbobenzyloxy derivative using benzyl chloroformate followed byalkylation of the alcohol using ethyl bromoacetate and potassiumt-butoxide, reduction of the ester using lithium borohydride intetrahydrofuran and deprotection of the nitrogen by hydrogenation in thepresence of palladium on carbon. In addition we prefer the case wherethe alcohols R³ and R⁴ are protected as an isopropylidene ring.

[0075] The amines of formula (m) can be prepared using proceduresdescribed in H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68, 1247,P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1.Amines and Related Compounds; Optical Resolution and Information Centre:Manhattan College, Riverdale, N.Y., 1978, p 120, J. Vallgarda et al, J.Chem. Soc. Perkin 1, 1994, 461 or in International Patent Application WO9905143.

[0076] All novel intermediates form a further aspect of the invention.

[0077] Salts of the compounds of formula (I) may be formed by reactingthe free acid, or a salt thereof, or the free base, or a salt or aderivative thereof, with one or more equivalents of the appropriate base(for example ammonium hydroxide optionally substituted by C₁₋₆-alkyl oran alkali metal or alkaline earth metal hydroxide) or acid (for examplea to hydrohalic (especially HCl), sulphuric, oxalic or phosphoric acid).The reaction may be carried out in a solvent or medium in which the saltis insoluble or in a solvent in which the salt is soluble, e.g. water,ethanol, tetrahydrofuran or diethyl ether, which may be removed invacuo, or by freeze drying. The reaction may also be a metatheticalprocess or it may be carried out on an ion exchange resin. The non-toxicphysiologically acceptable salts are preferred, although other salts maybe useful, e.g. in isolating or purifying the product.

[0078] The compounds of the invention act as P_(2T) (P2Y_(ADP) orP²T_(AC)) receptor antagonists. Accordingly, the compounds are useful intherapy, including combination therapy, particularly they are indicatedfor use as: inhibitors of platelet activation, aggregation anddegranulation, promoters of platelet disaggregation, anti-thromboticagents or in the treatment or prophylaxis of unstable angina, primaryarterial thrombotic complications of atherosclerosis such as thromboticor embolic stroke, transient ischaemic attacks, peripheral vasculardisease, myocardial infarction with or without thrombolysis, arterialcomplications due to interventions in atherosclerotic disease such asangioplasty, including coronary angioplasty (PTCA), endarterectomy,stent placement, coronary and other vascular graft surgery, thromboticcomplications of surgical or mechanical damage such as tissue salvagefollowing accidental or surgical trauma, reconstructive surgeryincluding skin and muscle flaps, conditions with a diffusethrombotic/platelet consumption component such as disseminatedintravascular coagulation, thrombotic thrombocytopaenic purpura,haemolytic uraemic syndrome, thrombotic complications of septicaemia,adult respiratory distress syndrome, anti-phospholipid syndrome,heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venousthrombosis such as deep vein thrombosis, venoocclusive disease,haematological conditions such as myeloproliferative disease, includingthrombocythaemia, sickle cell disease; or in the prevention ofmechanically-induced platelet activation in vivo, such ascardiopulmonary bypass and extracorporeal membrane oxygenation(prevention of microthromboembolism), mechanically-induced plateletactivation in vitro, such as use in the preservation of blood products,e.g. platelet concentrates, or shunt occlusion such as in renal dialysisand plasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis, inflammatory boweldisease and organ graft rejection, conditions such as migraine,Raynaud's phenomenon, conditions in which platelets can contribute tothe underlying inflammatory disease process in the vascular wall such asatheromatous plaque formation/progression, stenosis/restenosis and inother inflammatory conditions such as asthma, in which platelets andplatelet-derived factors are implicated in the immunological diseaseprocess. Further indications include treatment of CNS disorders andprevention of the growth and spread of tumours.

[0079] According to the invention there is further provided the use of acompound according to the invention as an active ingredient in themanufacture of a medicament for use in the treatment or prevention ofthe above disorders. In particular the compounds of the invention areuseful for treating myocardial infarction, thrombotic stroke, transientischaemic attacks, peripheral vascular disease and stable and unstableangina, especially unstable angina. The invention also provides a methodof treatment or prevention of the above disorders which comprisesadministering to a person suffering from or susceptible to such adisorder a therapeutically effective amount of a compound according tothe invention.

[0080] The compounds may be administered topically, e.g. to the lungand/or the airways, in the form of solutions, suspensions, HFA aerosolsand dry powder formulations; or systemically, e.g. by oraladministration in the form of tablets, pills, capsules, syrups, powdersor granules, or by parenteral administration in the form of sterileparenteral solutions or suspensions, by subcutaneous administration, orby rectal administration in the form of suppositories or transdermally.

[0081] The compounds of the invention may be administered on their ownor as a pharmaceutical composition comprising the compound of theinvention in combination with a pharmaceutically acceptable diluent,adjuvant and/or carrier. Particularly preferred are compositions notcontaining material capable of causing an adverse, e.g. an allergic,reaction.

[0082] Dry powder formulations and pressurised HFA aerosols of thecompounds of the invention may be administered by oral or nasalinhalation. For inhalation the compound is desirably finely divided. Thecompounds of the invention may also be administered by means of a drypowder inhaler. The inhaler may be a single or a multi dose inhaler, andmay be a breath actuated dry powder inhaler.

[0083] One possibility is to mix the finely divided compound with acarrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcoholor another polyol. Suitable carriers include sugars and starch.Alternatively the finely divided compound may be coated by anothersubstance. The powder mixture may also be dispensed into hard gelatinecapsules, each containing the desired dose of the active compound.

[0084] Another possibility is to process the finelv divided powder intospheres which break up during the inhalation procedure. This spheronizedpowder may be filled into the drug reservoir of a multidose inhaler,e.g. that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive compound with or without a carrier substance is delivered to thepatient.

[0085] The pharmaceutical composition comprising the compound of theinvention may conveniently be tablets, pills, capsules, syrups, powdersor granules for oral administration; sterile parenteral or subcutaneoussolutions, suspensions for parenteral administration or suppositoriesfor rectal administration.

[0086] For oral administration the active compound may be admixed withan adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol,starches such as potato starch, corn starch or amylopectin, cellulosederivatives, a binder such as gelatine or polyvinylpyrrolidone, and alubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, waxes, paraffin, and the like, and then compressed into tablets.If coated tablets are required, the cores, prepared as described above,may be coated with a concentrated sugar solution which may contain e.g.gum arabic, gelatine, talcum, titanium dioxide, and the like.Alternatively, the tablet may be coated with a suitable polymerdissolved either in a readily volatile organic solvent or an aqueoussolvent.

[0087] For the preparation of soft gelatine capsules, the compound maybe admixed with e.g. a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the compound using either theabove mentioned excipients for tablets, e.g. lactose, saccharose,sorbitol, mannitol, starches, cellulose derivatives or gelatine. Alsoliquid or semisolid formulations of the drug may be filled into hardgelatine capsules.

[0088] Liquid preparations for oral application may be in the form ofsyrups or suspensions, for example solutions containing the compound,the balance being sugar and a mixture of ethanol, water, glycerol andpropylene glycol. Optionally such liquid preparations may containcolouring agents, flavourin-agents, saccharine andcarboxymethylcellulose as a thickening agent or other excipients knownto those skilled in art.

EXAMPLES

[0089] The invention is illustrated by the following non-limitingexamples.

[0090] In the examples the NMR spectra were measured on a Varian UnityInova 300 or 400 spectrometer and the MuS spectra were measured asfollows: EI spectra were obtained on a VG 70-250S or Finnigan MatIncos-XL spectrometer, FAB spectra were obtained on a VG70-250SEQspectrometer, ESI and APCI spectra were obtained on Finnigan Mat SSQ7000or a Micromass Platform spectrometer. Preparative HPLC separations weregenerally performed using a Novapak®, Bondapak® or Hypersil® columnpacked with BDSC-18 reverse phase silica. Flash chromatography(indicated in the Examples as (SiO₂)) was carried out using FisherMatrix silica, 35-70 μm. For examples which showed the presence ofrotamers in the proton NMR spectra only the chemical shifts of the majorrotamer are quoted.

Example 1

[0091][1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0092] a)[3aS-[1(E),3aα,6α,7aβ]]-1-[3-(4-Fluorophenyl)-1-oxo-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

[0093] A mixture of 3-(4-fluorophenyl)-2-propenoic acid (3.0 g) andthionyl chloride (5.0 ml) was stirred at 70° C. for 1 hour, the reactionmixture was then concentrated under reduced pressure. The residue wasazeotroped twice with dichloromethane then dissolved in toluene (10 ml).To a suspension of sodium hydride (60% dispersion in oil; 0.99 g) intoluene (40 ml) was added a solution of[3aS-(3aα,6α,7aβ)]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide(3.89 g) in toluene (40 ml) and the mixture stirred for 30 minutes. Tothe reaction mixture was then added the solution described above and theresulting suspension was stirred for 16 hours. Water (200 ml) was added,the organics collected and the aqueous extracted into dichloromethane(3×100 ml). The organics were combined, dried and concentrated.Recrystallisation (ethanol) gave the subtitle compound as colourlessneedles (5.92 g).

[0094] MS (APCI) 364 (M+H⁺,100%)

[0095] b)[3aS-[1(1S*,2S*),3aα,6α,7aβ]]-1-[[2-(4-Fluorophenyl)cyclopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

[0096] A solution of diazomethane (2.9 g) in ether (150 ml) (prepared asdescribed in Vogel's Textbook of Practical Organic Chemistry, FifthEdition, Longman Scientific and Technical, p432) was added to a solutionof the product of step a) (5.90 g) and palladium(II) acetate (18 mg) indichloromethane (350 ml) at 0° C. and the reaction mixture stirred at 0°C. for 5 hours. Acetic acid (5 ml) was added and the reaction mixturewas then washed with saturated sodium bicarbonate solution (200 ml) andthe organics filtered through a plug of silica. After concentrating invacuo, the residue was recrystallised (ethanol) to give the subtitlecompound as colourless needles (3.81 g).

[0097] MS (APCI) 378 (M+H⁺,100%)

[0098] c) (1R-trans)-2-(4-Fluorophenyl)-cyclopropanecarboxylic Acid

[0099] A suspension of the product from step b) (3.74 g) and lithiumhydroxide monohydrate (4.11 g) in tetrahydrofuran (100 ml)/water (3 ml)was stirred at 50° C. for 24 hours. The reaction mixture wasconcentrated in vacuo, and the residue dissolved in water (100 ml),acidified with 2N HCl and extracted into dichloromethane (3×75 ml). Theorganics were dried and concentrated. Purification (SiO₂,isohexane:diethylether 2:1 as eluant) gave the subtitle compound as acolourless solid (1.78 g).

[0100] MS (APCI) 179 (M−H⁺,100%)

[0101] d) (1R-trans)-2-(4-Fluorophenyl)cyclopropanamine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

[0102] To a solution of the product from step c) (1.78 g) andtriethylamine (2.7 ml) in acetone/water (10:1, 23 ml) at 0° C. was addedethyl chloroformate (2.0 ml) over 5 min. The solution was maintained at0° C. for 30 minutes before addition of sodium azide (1.52 g) in water(6 ml). After a further hour, water (350 ml) was added and the reactionmixture extracted with toluene (3×100 ml). The organic extracts werecombined and dried, then heated at reflux for 2 hours behind a blastscreen. After cooling the solution, 6N HCl (50 ml) was added and themixture heated at reflux for 3 hours. Water (150 ml) was added and theaqueous phase basified with 2N NaOH (aq), then extracted intodichloromethane (3×100 ml). The organic phase was dried andconcentrated. The amine was dissolved in ethanol (5 ml) and a solutionof L-tartaric acid (1.48 g) in ethanol (20 ml) was added. After 20minutes the solid was collected affording the subtitle compound ascolourless needles (1.12 g).

[0103] NNIR δH (d₆-DMSO) 1.07-1.39 (1H, m), 1.22-1.29 (1H, m), 2.16-2.23(1H, m), 2.64-2.70 (1H, m), 3.95 (2H, s), 7.06-7.19 (4H, m)

[0104] e)[3aR-[3aα,4α,6α(1R*,2*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0105] N,N-Diisopropylethylamine (1.29 g) was added to a solution of[3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084)(1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml).The reaction mixture was stirred at room temperature for 3 hours, thenwashed with water, dried and evaporated. The residue was purified (SiO₂,ethyl acetate:isohexane 1:1 as eluent) to afford the subtitle compound(1.25 g).

[0106] MS (APCI) 515 (M+H⁺, 100%)

[0107] f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0108] 3-Chloroperoxybenzoic acid (70%, 1.8 g) was added to a suspensionof the product of step e) (1.25 g) in ethanol (25 ml) and the resultingsolution stirred at room temperature for 2 hours. The reaction mixturewas concentrated and the residue taken up in ethyl acetate (500 ml),washed with 10% aqueous sodium metabisulfite solution (2×100 ml) and 10%aqueous sodium bicarbonate solution (2×100 ml) then dried andconcentrated to afford the subtitle compound (1.4 g).

[0109] MS (APCI) 547 (M+H⁺, 100%)

[0110] g)[[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropy)lthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0111] Sodium hydrosulfide hydrate (1.4 g) was added to a solution ofthe product of step f) (1.4 g) in dimethyl sulphoxide (20 ml) and thesolution stirred at room temperature for 1.5 hours. Brine (150 ml) wasadded and the mixture acidified with acetic acid then extracted withethyl acetate (3×100 ml). The organic phase was dried and concentratedand the residue azeotroped with toluene (3×100 ml). The residue wasdissolved in N,N-dimethylformamide (20 ml) thenN,N(-diisopropylethylamine (0.33 g) and 3,3,3-trifluoropropylbromide(0.48 g) added. After stirring at 50° C. for 30 minutes the reactionmixture was diluted with ethyl acetate (100 ml) then washed with aqueousbrine (3×100 ml), dried and concentrated then the residue purified(SiO₂, isohexane:ethyl acetate 1:1 as eluant) to afford the subtitlecompound (1.4 g).

[0112] MS (APCI) 569 (M+H⁺, 100%)

[0113] h)[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0114] A solution of the product from step g) (1.4 g) in trifluoroaceticacid (10 ml) and water (2 ml) was stirred at room temperature for 1hour. The reaction mixture was diluted with ethyl acetate (400 ml) thenwashed with sodium bicarbonate solution (400 ml), dried and evaporated.The residue was purified (SiO₂, methanol:chloroform 3:47 as eluant) toafford the title compound (0.44 g).

[0115] MS (APCI) 529. (M+H⁺,100%)

[0116] NMR δH (d₆-DMSO) 9.42 (1H, d), 7.27-7.22 (2H, m), 7.14-7.08 (2H,m), 5.01-4.95 (2H, m), 4.73-4.70 (2H, m), 4.44-4.41 (1H, m), 3.87-3.84(1H, m), 3.50-3.45 (2H, m), 3.26-3.13 (3H, m), 2.60-2.55 (1H, m),2.28-2.20 (2H, m), 2.10-2.06 (1H, m), 1.90-1.80 (1H, m), 1.49-1.46 (1H,m), 1.33-1.30 (1H, m).

Example 2

[0117][1R-[1α,2α,3β(1R*,1S*),5β]]-3-(7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0118] a)[3aS-[1(E),3aα,6α,7aβ]]-1-[3-(3,4-Difluorophenyl)-1-oxo-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

[0119] The subtitle compound was prepared according to the method ofExample 1, step a) using 3-(3,4-difluorophenyl)-2-propenoic acid.

[0120] MS (APCI) 382 (M+H⁺, 100%)

[0121] b)[3aS-[1(1S*,2S*),3aα,6α,7aβ]]-1-[[2-(3,4-Difluorophenyl)cyclopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

[0122] The subtitle compound was prepared according to the method ofExample 1, step b) using the product of step a).

[0123] MS (APCI) 396 (M+H⁺, 100%)

[0124] c)(1R-trans)-2-(3,4-Difluorophenyl)-cyclopropane Carboxylic Acid

[0125] The subtitle compound was prepared according to the method ofExample 1, step c) using the product of step b).

[0126] NMR δH (CDCl₃) 7.06 (1H, dt, J=10.0, J=8.5 Hz), 6.93-6.80 (2H,m), 2.58-2.52 (1H m), 1.88-1.82 (1H, m), 1.66 (1H, dt, J=9.2, J=5.2 Hz),1.34 (1H, ddd, J=8.5, J=6.5, J=4.8 Hz).

[0127] d)(1R-trans)-2-(3,4-Difluorophenyl)cyclopropanamine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

[0128] The subtitle compound was prepared according to the method ofExample 1, step d) using the product of step c).

[0129] MS (APCI) 170 (M+H⁺, 100%)

[0130]e)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amno]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0131] Isoamyl nitrite (5.1 ml) was added to a solution of[3aR-(3aα,4α,6α,6aα)]-6-[[5-amino-6-Chloro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]-amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084)(8.1 g) in acetonitrile (1000 ml) and the solution heated at 70° C. for1 hour. The cooled reaction mixture was concentrated and purified (SiO₂,dichloromethane:ethyl acetate 4:1 as eluant) to afford an intermediatewhich was converted to the subtitle compound by the method of example 1,step e) using the product of step d).

[0132] MS (APCI) 587 (M+H⁺, 100%)

[0133] f)[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0134] Prepared according to the method of example 1, step h) using theproduct of step e).

[0135] MS (APCI) 547 (M+H⁺, 100%)

[0136] NMR δH (d₆-DMSO) 9.43 (1H, d), 7.35-7.28 (2H, m), 7.14-7.02 (1H,m), 5.01-4.96 (2H, m), 4.72-4.69 (2H, m), 4.42 (1H, q), 3.87-3.84 (1H,m), 3.50-3.44 (2H, m), 3.25-3.12 (3H, m), 2.58-2.50 (2H, m), 2.28-2.21(3H, m), 1.85-1.80 (1H, m), 1.52-1.50 (1H, m), 1.39-1.37 (1H, m).

Example 3

[0137][1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol,

[0138] a)(1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate

[0139] To a suspension of ether washed sodium hydride (60% dispersion inoil; 0.31 g) in tetrahydrofuran (30 ml) was added imidodicarbonic acidbis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40° C.for 1 hour. To the mixture, at ambient temperature, was then added(1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) andtetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixturewas stirred for 24 hours then purified (SiO₂, ethyl acetate:hexane 1:9as eluant) to give the subtitle compound as a colourless solid (0.90 g).

[0140] NMR δH (d₆-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4Hz), 2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq,J=8.0, 1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77 (2H, m).

[0141] b)[1R-(1α,2β,3β,4α)]-2,3,4-Trihydroxy-cyclopentenylimidodicarbonic Acid,bis(1,1-dimethylethyl) Ester

[0142] To a solution of the product of step a) (17.1 g) intetrahydrofuran (500 ml)/water (50 ml) was addedN-methylmorpholine-N-oxide (9.4 g) followed by osmium tetroxide (10 ml,2.5% solution in t-butanol). The mixture was stirred at room temperaturefor 4 days then treated with sodium hydrosulphite (6.0 g). Thesuspension was filtered through celite and the product purified (SiO.,ethyl acetate:hexane 1:1 as eluant) to afford the subtitle compound(19.1 g)

[0143] NMR δH (d₆-DMSO) 1.44 (18H, s), 1.46-1.60 (1H, m), 1.97-2.05 (1H,m), 3.55-3.58 (1H, m), 3.66-3.73 (1H, m), 4.11-4.21 (2H, m), 4.54 (1H,d, J=4.8 Hz), 4.56 (1H, d, J=5.9 Hz), 4.82 (1H, d, J=4.6 Hz)

[0144] c)[3aR-(3aα,4α,6α,6aα)]-6-Amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,Hydrochloride

[0145] The product from step b) (17.4 g) in 6M HCl (100 ml)/methanol(500 ml) was stirred for 18 hours. The mixture was evaporated and thenazeotroped with toluene (4×200 ml) to give a colourless powder (8.7 g).This solid was suspended in acetone (250 ml) containing2,2-dimethoxypropane (25 ml) and cHCl (0.2 ml) then heated under refluxfor 2 hours. The mixture was cooled, evaporated and azeotroped withtoluene (3×200 ml). The residue was dissolved in 20% aqueous acetic acidand stirred for 2 hours. The mixture was evaporated and azeotroped withtoluene (4×200 ml) to afford the subtitle compound (10.1 g).

[0146] MS (APCI) 174 (M+H⁺, 100%)

[0147] d)[3aR-(3aα,4α,6α,6aα)]-6-[[6-Chloro-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl4H-cyclopenta-1,3-dioxol-4-ol

[0148] A solution of the product from step c) (10.0 g) andNN-diisopropylethylamine (35 ml) in tetrahydrofuran (600 ml) was stirredfor 1 hour. The mixture was filtered and the solution was added over 1hour to a solution of 4,6-dichloro-5-nitro-2-(propylthio)-pyrimidine(prepared as described in International Patent Application WO 9703084)(25.6 g) in tetrahydrofuran (1000 ml) and stirred for a further 2 hours.The solvent volume was reduced in vacuo and ethyl acetate was added(1000 ml). The mixture was washed with water and the organic layers weredried, evaporated and purified (SiO₂, isohexane-ethyl acetate as eluant)to afford the subtitle compound (14.2 g).

[0149] MS (APCI) 405 (M+H⁺, 100%)

[0150] e)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-Chloro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0151] Iron powder (3.0 g) was added to a stirred solution of theproduct of step d) (2.7 g) in acetic acid (100 ml). The reaction mixturewas stirred at room temperature for 2 hours, concentrated to halfvolume, diluted with ethyl acetate and washed with water. The organicphase was dried and concentrated to afford the subtitle compound (2.0g).

[0152] MS (APCI) 375 (M+H⁺, 100%)

[0153] f)[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0154] Isoamyl nitrite (1.1 ml) was added to a solution of the productof step e) (2.0 g) in acetonitrile (100 ml) and the solution heated at70° C. for 1 hour. The cooled reaction mixture was concentrated andpurified (SiO₂, ethyl acetate:isohexane 1:3 as eluant) to afford thesubtitle compound (1.9 g).

[0155] MS (APCI) 386 (M+H⁺, 100%)

[0156] g)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0157] The product of step f) (13.2 g) in tetrahydrofuran (200 ml)containing 0.88 ammonia (5 ml) was stirred for 2 hours then concentratedto dryness and the residue partitioned between water and ethyl acetate.The organics were dried and then concentrated to afford the subtitlecompound (12.5 g).

[0158] MS (APCI) 367 (M+H⁺, 100%).

[0159] h)[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticAcid, Methyl Ester

[0160] To a solution of the product of step g) (0.50 g) intetrahydrofuran (25 ml) at 0° C., was added butyllithium (0.62 ml of2.5N in hexanes). After 20 minutes, the suspension was treated with asolution of trifluoromethanesulfonyloxy-acetic acid methyl ester (0.34g) (prepared according to the method of Biton, Tetrahedron, 1995, 51,10513) in tetrahydrofuran (10 ml). The resulting solution was allowed towarm to room temperature then concentrated and purified (SiO₂, ethylacetate:hexane 4:6 as eluant) to afford the subtitle compound (0.25 g).

[0161] MS (APCI) 439 (M+H⁺, 100%).

[0162] i)[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticAcid, Methyl Ester

[0163] The product from step h) (1.1 g) and isoamylnitrite (2.4 ml) inbromoform (30 ml) was heated at 80° C. for 30 minutes. The cooledreaction mixture-was purified (SiO₂, ethyl acetate:isohexane 1:4 aseluant) to afford the subtitle compound (0.44 g).

[0164] MS (APCI) 502/4 (M+H⁺), 504 (100%).

[0165] j)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]aceticAcid, Methyl Ester

[0166] To a mixture of the products from step i) (0.80 g) and Example 2,step d) (0.61 g) in dichloromethane (25 ml) was addedN,N-diisopropylethylamine (0.85 ml). The resulting solution was stirredat room temperature for 16 hours then concentrated in vacuo.Purification (SiO₂, isohexane:ethylacetate 3:1 as eluant) gave thesubtitle compound as a colourless foam (0.77 g).

[0167] MS (APCI) 591 (M+H⁺, 100%)

[0168] k)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-([7-[2-(3,4-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

[0169] DIBAL-H® (1.0M solution in hexanes, 5.15 ml) was added to anice-cooled solution of the product of step j) (0.76 g) intetrahydrofuran (1 ml) and the solution stirred at this temperature for2 hours. The reaction mixture was concentrated in vacuo and the residuewas dissolved in ethyl acetate (75 ml). A saturated aqueous solution ofsodium potassium tartrate (75 ml) was added and the mixture stirredvigorously for 16 hours. The organics were collected and the aqueousre-extracted with ethyl acetate (2×50 ml). The combined organics weredried and concentrated and the residue purified (SiO₂,isohexane:ethylacetate 1:1 as eluant) to give the subtitle compound(0.63 g).

[0170] MS (APCI) 563 (M+H⁺,100%)

[0171] l)[1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-(2-(3,4-Difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

[0172] Prepared according to the method of example 1, step h) using theproduct of step k).

[0173] MS-(APCI) 523 (M+H⁺, 100%)

[0174] NMR δH (d₆-DMSO) 8.95 (1H, d, J=3.3 Hz), 7.39-7.21 (2H, m),7.10-7.00 (1H, m), 5.12 (1H, d, J=6.4 Hz), 5.05 (1H, d, J=3.6 Hz), 4.96(1H, q, J=9.0 Hz), 4.62-4.54 (2H, m), 3.95 (1H, br s), 3.79-3.73 (1H,m), 3.55-3.47 (4H, m), 3.20-3.13 (1H, m), 2.98-2.81 (2H, m), 2.63 (1H,dt, J=13.6, 8.5 Hz), 2.29-2.21 and 2.16-2.69 (1H, m), 2.07-2.00 (1H, m),1.73-1.33 (4H, m), 0.99 (3H, t, J=7.4 Hz).

Example 4

[0175][1R-[1α,2α,3β(1R*,2S*),5β]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0176] a)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0177] Prepared according to the method of Example 3, step g) using[3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(prepared as described in International Patent Application WO 9703084).The crude product was purified (SiO₂, methanol:dichloromethane 1:19 aseluant) to give the subtitle compound.

[0178] MS (APCI) 381 (M+H⁺, 100%).

[0179] b)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0180] Prepared according to the method of example 1, step f) using theproduct of step a).

[0181] MS (APCI) 413 (M+H⁺, 100%).

[0182] c)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

[0183] 1-Butanethiol (2.38 ml) in DMF (25 ml) was added to a suspensionof sodium hydride (60%, 1.09 g) in DMF (50 ml). After 1 hour a solutionof the product of step b) (3.66 g) in DMF (65 ml) was added dropwise andthe resulting mixture was stirred overnight. The reaction mixture wasadded slowly to saturated aqueous sodium bicarbonate (1000 ml) and thenextracted into ethyl acetate (3×200 ml). The organic phase was dried(MgSO₄) and concentrated in vacuo and the residue purified (SiO₂,methanol:dichloromethane 1:19 as eluant) to give the subtitle compound(3.32 g).

[0184] MS (APCI) 395 (M+H⁺, 100%).

[0185] d)[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

[0186] To a solution of the product from step c) (3.3 g) indichloromethane (50 ml), was added pyridine (2.7 ml),4-dimethylaminopyridine (0.4 g) and acetic anhydride (2.0 ml). Themixture was stirred at room temperature overnight, concentrated in-vacuoand purified (SiO₂, diethyl ether:isohexane 3:2 as eluent) to give thesubtitle compound (2.7 g).

[0187] MS (APCI) 437 (M+H⁺, 100%).

[0188] e)[3aR-(3aα,4α,6α,6aα)]-6-[7-Bromo-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin.3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

[0189] Prepared according to the method of example 3, step i) using theproduct of step d).

[0190] MS (APCI) 500/502 (M+H⁺), 500 (100%).

[0191] f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate

[0192] Prepared according to the method of example 3, step j) using theproduct of example 2, step d) and the product of step e).

[0193] MS (APCI) 589 (M+H⁺, 100%).

[0194] g)[1R-[1α,2α,3β(1R*,2S*),5β]]-3-(5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol

[0195] The product of step f) (0.64 g) in 80% aqueous acetic acid (30ml) was heated at 80° C. for 1 hour. The cooled mixture was poured intosaturated sodium bicarbonate solution and extracted into ethyl acetate.The organic phase was dried and concentrated in vacuo to give a gumwhich was dissolved in methanol (50 ml)/10% aqueous potassium carbonatesolution (3 ml). The solution was stirred for 30 minutes, neutralisedwith acetic acid, and concentrated in vacuo. Purification (SiO₂,methanol:dichloromethane 1:19 as eluent) gave a solid which wasrecrystallised (acetonitrile) to give the title compound (0.25 g).

[0196] MS (APCI) 507 (M+H⁺, 100%).

[0197] NMR 5H (d₆-DMSO) 9.34 (1H, br), 7.40-7.23 (2H, m), 7.11-7.00 (1H,m), 5.06-4.93 (2H, m), 4.764.67 (2H, m), 4.484.38 (1H, m), 3.91-3.84(1H, m), 3.56-3.39 (2H, m), 3.21-3.08 (1H, m), 3.03-2.83 (2H, m),2.32-2.17 (1H, m), 2.17-2.03 (2H, m), 1.91-1.77 (1H, m), 1.71-1.32 (4H,m), 1.32-1.17 (2H, m), 0.81 (3H, t).

Example 5

[0198][1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol

[0199] a)[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-(7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0200] Prepared according to the method of example 1, step e) using theproduct of example 1, step d) and the product of example 3 step f).

[0201] MS (APCI) 501 (M+H⁺, 100%).

[0202] b)[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0203] Prepared according to the method of example 1, step f) using theproduct of step a).

[0204] MS (APCI) 532 (M+H⁺, 100%).

[0205] c)[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropy]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0206] Prepared according to the method of example 4 step c) using theproduct of step b).

[0207] MS (APCI) 515 (M+H⁺, 100%).[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-(5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol

[0208] Prepared according to the method of example 1 step h) using theproduct of step c).

[0209] MS (APCI) 575 (M+H⁺, 100%).

[0210] NMR δH (d₆-DMSO) 7.26-7.22 (2H, m), 7.11 (2H, t), 4.99-4.90 (1H,m), 4.67-4.63 (1H, m), 3.93 (1H, s), 3.77 (1H, bs), 3.35-3.13 (1H, m),3.00-2.80 (2H, m), 2.59-2.51 (1H, m), 2.15-2.11 (1H, m), 1.91-1.86 (1H,m), 1.53-1.41 (3H, m), 1.35-1.30 (1H, m), 1.22 (2H, sex), 0.80 (3H, t).

Example 6

[0211][1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5d]pyrimnidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

[0212] a)[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]aiino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

[0213] The subtitle compound was prepared according to the method ofExample 1, step f) using the product of Example 3, step 1.

[0214] MS(APCI) 555(M+H⁺, 100%)

[0215] b)[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimiidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol

[0216] The title compound was prepared according to the method ofExample 1, step g) using the product of step a).

[0217] MS(APCI) 555 (M+H⁺, 100%)

[0218] NMR δH (d₆-DMSO) 9.45 (1H, d), 7.36-7.05 (3H, m), 5.05 (1H, d),5.02 (1H, d), 4.95 (1H, m), 4.60 (2H, m), 3.95 (1H, m), 3.86 (1H, m),3.47 (4H, m), 3.30-3.11 (3H, m), 2.63-2.49 (3H, m), 2.19 (1H, m), 2.00(1H, m), 1.53 (1H, m), 1.40 (1H, m).

Example 7

[0219][1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol

[0220] a)(1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thiol-4-pyrimidinyl]amino]-2-cyclopenten-1-yl]oxy]-aceticAcid, Ethyl Ester

[0221] A solution of sodium azide (4.70 g) in degassed water (25 ml) wasadded to a solution of (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate(9.99 g) in tetrahydrofuran (60 ml) and stirred for 10 min.Tetrakis(triphenylphosphine)palladium(0) (365 mg) was added and stirredfor 10 min. The aqueous layer was separated and extracted twice withethyl acetate. The combined organic layers were dried (MgSO₄),concentrated and purified on a short column (SiO₂, ethylacetate:isohexane 1:2 as eluant) to afford a yellow oil. This wasdissolved in tetrahydrofuran (25 ml) and slowly added to a suspension ofsodium hydride (2.94 g, 60% dispersion in oil) in tetrahydrofuran (60ml) at −78° C. A solution of ethyl bromoacetate (8.2 ml) intetrahydrofuran (5 ml) was added and the mixture was allowed to warm to20° C. and stirred for 30 min. Aqueous ammonium chloride solution wasadded and the mixture was extracted with ether. The organic layers weredried (MgSO₄), concentrated and purified (SiO₂, ether:isohexane 1:5 aseluant) to afford a colourless oil. A solution of this oil andtriphenylphosphine (17.89 g) in tetrahydrofuran (90 ml) was stirred for10 min. Water (15 ml) was added and the solution was stirred for 18hours. The solvent was removed in vacuo and the residue azeotroped withtoluene then purified (SiO₂, ethyl acetate then ethylacetate—methanol—ammonia (90:9:1) as eluant) to afford a pale yellow oil(7.14 g).

[0222] A solution of this compound in tetrahydrofuran (50 ml) was addedover 25 min to a solution of4,6-dichloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio] pyrimidine(prepared as described in International Patent Application WO 9703084)(24.8 g) and N,N-diisopropylethylamine (77.5 ml) in dry tetrahydrofuran(100 ml) and then stirred for 30 minutes. Water was added and themixture was extracted with ether (three times). The organic layers weredried (MgSO₄), concentrated and purified (SiO., ethyl acetate:isohexane1:4 as eluant) to afford the subtitle compound (7.39 g).

[0223] MS (APCI) 367/9 (M-(EtO₂CCH₂O)⁺), 367 (100%)

[0224] b) (1S-cis)2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticAcid, Ethyl Ester

[0225] Prepared according to the method of example 3, steps e) and f)using the product of step a).

[0226] MS (APCI) 348/50 (M-(EtO₂CCH₂O)⁺), 348 (100%).

[0227] c) [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticAcid, Ethyl Ester

[0228] Prepared according to the method of example 3, step g) using theproduct of step b).

[0229] MS (APCI) 433 (M+H⁺, 100%).

[0230] d) [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thiol-3H-1,2,3-triazolo(4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-1-ethanol

[0231] Prepared according to the method of example 3, step k) using theproduct of step c).

[0232] MS (APCI) 391 (M+H⁺, 100%).

[0233] e)[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol

[0234] A solution of the product from step d) (454 mg), osmium tetroxide(0.17 ml of 0.1M solution in t-butanol), N-methylmorpholine N-oxide (210mg) and pyridine (0.09 ml) in acetone (5 ml) and water (1 ml) was heatedat 70° C. for 5 hours. Sodium hydrosulfite (330 mg) in water (1 ml) wasadded, the solvent was remove in vacuo and the residue azeotroped withtoluene. A solution of this and p-toluenesulfonic acid (50 mg) inacetone (5 ml) and 2,2-dimethoxypropane (2 ml) was stirred for 3 h. Thesolvent was remove in vacuo, aq sodium hydrogen carbonate solution addedand the mixture was extracted with ethyl acetate. The organic layerswere dried (MgSO₄), concentrated and purified (SiO₂,isohexane:acetone5:2 as eluant) to afford the subtitle compound as a white solid (367mg).

[0235] MS (APCI) 465 (M+H⁺, 100%)

[0236] f)[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Bromo-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol

[0237] Prepared according to the method of Example 3, step i) using theproduct of step e).

[0238] MS (APCI) 528/30 (M+H⁺), 528 (100%)

[0239] g)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-2-[6-(7-Phenylcyclopropyl)amino]-S-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol

[0240] Prepared according to the method of Example 3, step j) using theproduct of step f) and (1R-trans)-2-phenyl-cyclopropanamine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L.A. Mitscher et al., J. Med. Chem. 1986, 29, 2044).

[0241] MS (APCI) 581 (M+H⁺, 100%)

[0242] h)[1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diolPrepared according to the method of Example 1, step h) using the productof step g).

[0243] MS (APCI) 540 (M+H⁺, 100%).

[0244] NMR δH (d₆-DMSO) 7.35-7.16 (5H, m), 4.97 (1H, q), 4.62-4.54 (1H,m), 3.98-3.92 (1H, m), 3.78-3.72 (1H, m), 3.55-3.44 (4H, m), 3.26-3.19(2H, m), 3.16-3.07 (1H, m), 2.70-2.61 (1H, m), 2.58-2.52 (1H, m),2.23-2.18 (1H, m), 2.05-1.97 (1H, m), 1.86 (1H, s), 1.54-1.46 (1H, m),1.38-1.30 (1H, m).

Example 8

[0245][1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]cyclopentane-1,2,3-triol

[0246] a)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-([7-((3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0247] The subtitle compound was prepared according to the method ofExample-1, step e) using the product of Example 3, step f) and theproduct of example 2, step d).

[0248] MS (APCI) 519 (M+H⁺, 100%).

[0249] b)[3aR-[3aα,4α,6α(1R*,2S*),6aα]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]axino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0250] The subtitle compound was prepared according to the method ofExample 1, step f) using the product of step a).

[0251] MS (APCI) 551 (M+H⁺, 100%).

[0252] c)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0253] The subtitle compound was prepared according to the method ofExample 4, step c) using the product of step b).

[0254] MS (APCI) 533 (M+H⁺, 100%)

[0255] d)[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol

[0256] The title compound was prepared according to the method ofExample 1, step h) using the product of step c).

[0257] NMR δH (d₆-DMSO) 7.15-6.98 (3H, m), 6.67 (1H, s), 5.11-5.09 (1H,m), 4.82-4.76 (1H, m), 4.34-4.21 (3H, m), 3.7 (1H, s), 3.2-2.92 (4H, m),2.77 (1H, m), 2.42-2.36 (1H, m), 2.2-2.18 (1H, m), 1.42-1.25 (6H, m),0.9 (3H, q).

[0258] MS (APCI) 493 (M+H⁺, 100%)

Example 9

[0259][1S-(1α,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)a-no]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol

[0260] a)[3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicAcid, Phenylmethyl Ester

[0261] Potassium carbonate (39.3 g) was added to a suspension of[3aR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,hydrochloride, (prepared as described in WO 9905142) (27.1 g) in4-methyl-2-pentanone (SOOml). Water (150 ml) was then added followed bydropwise addition of benzyl chloroformate (23.1 g). The reaction mixturewas stirred at room temperature for 4 hours before the organic phase wasseparated. The aqueous phase was extracted with 4-methyl-2-pentanone(2×50 ml). The combined organics were concentrated and the residue waspurified (SiO₂, dichloromethane:methanol, 95:5 to 90:10 as eluant) togive the subtitle compound (39.23 g).

[0262] NMR δH (CDCl₃) 7.32 (5H, m), 5.65 (1H, br s), 5.10 (2H, br s),4.59 (1H, d), 4.48 (1H, d), 4.27 (1H, m), 4.19 (1H, br m), 2.24 (1H, brs), 1.69 (1H, d), 1.41 (3H, s), 1.26 (3H, s).

[0263] b)[3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicAcid, Phenylmethyl Ester

[0264] Potassium tert-butoxide (3.6 g) in tetrahydrofuran (20 ml) wasadded over 5 minutes to a solution of the product from step a) (39.23 g)in tetrahydrofuran (200 ml). After 15 minutes, ethyl bromoacetate (3.7ml) in tetrahydrofuran (10 ml) was added dropwise. The mixture wasstirred at 0° C. for 10 minutes, then further ethyl bromoacetate wasadded (3.7 ml×4). The reaction mixture was stirred at 0° C. a further 2hours. Lithium borohydride (2.79 g) was then added portionwise to theresulting suspension and the reaction mixture was stirred at <5° C. for16 hours. Glacial acetic acid (23 g) was added dropwise to the coldmixture. After stirring for 30 minutes, water (100 ml) was addeddropwise and the resulting mixture was stirred for 30 minutes. Thephases were then separated and the aqueous phase was extracted withethyl acetate. The combined organics were washed with saturated sodiumbicarbonate and brine, dried and concentrated. The residue was purified(SiO₂, ethyl acetate:hexane, 25:75 to 50:50 as eluant) to give thesubtitle compound (38.6 g).

[0265] MS (APCI) 218 (M+H⁺, 100%).

[0266] c)) [3aR-(3aα,4α,6α,6aα)]-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

[0267] A slurry of 5% palladium on charcoal (4 g) in ethanol was addedto a solution of the product from step b) (39.96 g) in ethanol (250 ml)and the mixture was hydrogenated at 1.2 bar for 20 hours. The catalystwas filtered off and the filtrate was concentrated to give the subtitlecompound (23.65 g).

[0268] MS (APCI) 160 (M+H⁺, 100%).

[0269] d) 2-(Butylthio)-4,6-dichloropyrimidine-5-amine

[0270] The subtitle compound was prepared according to the method ofexample 3, step e) using 2-(butylthio)-4,6-dichloro-5-nitro-pyrimidine(prepared as described in DE 2223644).

[0271] NMR δH (CDCl₃) 4.20 (2H, br s), 3.10 (2H, t), 1.70 (2H, m), 1.47(2H, m), 0.95 (3H, t).

[0272] e)[3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-Amino-2-(butylthio)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol

[0273] The subtitle compound was prepared according to the method ofexample 3, step d) using the products of steps c) and d).

[0274] MS (APCI) 433 (M+H⁺, 100%).

[0275] f)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ylloxy]-ethanol

[0276] The subtitle compound was prepared according to the method ofExample 3, step f) using the product of step e).

[0277] NMR δH (CDCl₃) 5.53 (1H, m), 5.21 (1H, m), 4.88 (1H, d), 4.05(1H, m), 3.59 (4H, m), 3.24 (2H, t), 2.70 (1H, m), 2.53 (1H, m), 2.13(1H, t), 1.79 (2H, m), 1.55 (5H, m), 1.37 (3H, s), 0.98 (3H, t).

[0278] g)(3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol

[0279] The subtitle compound was prepared according to the method ofExample 3, step j) using the product of step f).

[0280] MS (APCI) 541 (M+H⁺, 100%).

[0281] h)[1S-[1α,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)anino]-3H-1,2,3-triazolo[4,5-d]pyrirridin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol

[0282] The title compound was prepared according to the method ofexample 1, step h) using the product of step g).

[0283] MS (APCI) 501 (M+H⁺, 100%)

[0284] NMR δH (d₆-DMSO) 9.33 (1H, d), 7.30 (2H, m), 7.18 (3H, m), 5.12(1H, d), 5.04 (1H, d), 4.96 (1H, q), 4.59 (2H, m), 3.94 (1H, s), 3.76(1H, m), 3.51 (4H, m), 3.22 (1H, m), 2.98 (1H, m), 2.86 (1H, m), 2.65(1H, m), 2.14 (1H, m), 2.05 (1H, m), 1.21-1.53 (6H, m), 0.80 (3H, t).

[0285] Pharmacological Data

[0286] The preparation for the assay of the P_(2T) (P2Y_(ADP) orP2T_(AC)) receptor agonist/antagonist activity in washed human plateletsfor the compounds of the invention was carried out as follows.

[0287] Human venous blood (100 ml) was divided equally between 3 tubes,each containing 3.2% trisodium citrate (4 ml) as anti-coagulant. Thetubes were centrifuged for 15 minutes at 240G to obtain a platelet-richplasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize theplatelets during the washing procedure. Red cell free PRP was obtainedby centrifugation for 10 minutes at 125G followed by furthercentrifugation for 15 minutes at 640G. The supernatant was discarded andthe platelet pellet resuspended in modified, Calcium Free Tyrodesolution (10 ml) (CFT), composition: NaCl 137mM, NaHCO₃ 11.9mM, NaH₂PO₄0.4 mM, KCl 2.7 mM, MgCl₂ 1.1 ml, dextrose 5.6 mM, gassed with 95% O₂/5%CO₂ and maintained at 37° C. Following addition of a further 300 ng/mlPGI₂, the pooled suspension was centrifuged once more for 15 minutes at640G. The supernatant was discarded and the platelets resuspendedinitially in 10 ml CFT with further CFT added to adjust the finalplatelet count to 2×10⁵/ml. This final suspension was stored in a 60 mlsyringe at 3° C. with air excluded. To allow recovery fromPGI₂-inhibition of normal function, platelets were used in aggregationstudies no sooner than 2 hours after final resuspension.

[0288] In all studies, 3 ml aliquots of platelet suspension were addedto tubes containing CaCl₂ solution (60 μl of 50 mM solution with a finalconcentration of 1 mM). Human fibrinogen (Sigma, F 4883) and8-sulphophenyltheophylline (8-SPT which was used to block any Pi-agonistactivity of compounds) were added to give final concentrations of 0.2mg/ml (60 μl of 10 mg/ml solution of clottable protein in saline) and300 nM (10 μl of 15 multi solution in 6% glucose), respectively.Platelets or buffer as appropriate were added in a volume of 150 μl tothe individual wells of a 96 well plate. All measurements were made intriplicate in platelets from each donor.

[0289] The agonist/antagonist potency was assessed as follows.

[0290] Aggregation responses in 96 well plates were measured using thechange in absorbance given by the plate reader at 660 nm. Either aBio-Tec Ceres 900C or a Dynatech MRX were used as the plate reader.

[0291] The absorbance of each well in the plate was read at 660 nm toestablish a baseline figure. Saline or the appropriate solution of testcompound was added to each well in a volume of 10 μl to give a finalconcentration of 0, 0.01, 0.1, 1, 10 or 100 mM. The plate was thenshaken for 5 min on an orbital shaker on setting 10 and the absorbanceread at 660 nm. Aggregation at this point was indicative of agonistactivity of the test compound. Saline or ADP (30 mM; 10 μl of 450 mM)was then added to each well and the plate shaken for a further 5 minbefore reading the absorbance again at 660 nm.

[0292] Antagonist potency was estimated as a % inhibition of the controlADP response to obtain an IC₅₀. Compounds exemplified have pIC₅₀ valuesof more than 5.0.

1. A compound of formula (I)

wherein: R¹ is C₃₋₅ alkyl optionally substituted by one or more halogenatoms; R² is a phenyl group, optionally substituted by one or morefluorine atoms; R³ and R⁴ are both hydroxy; R is XOH, where X is CH₂,OCH₂CH₂ or a bond; or a pharmaceutically acceptable salt or solvatethereof, or a solvate of such a salt provided that: when X is CH₂ or abond, R¹ is not propyl. when X is CH₂ and R¹ is CH₂CH₂CF₃, butyl orpentyl, the phenyl group at R² must be substituted by fluorine. when Xis OCH₂CH₂ and R¹ is propyl, the phenyl group at R² must be substitutedby fluorine.
 2. A compound according to claim 1 in which R¹ is3,3,3,-trifluoropropyl, butyl or propyl.
 3. A compound according toclaims 1 or 2 in which R² is phenyl or 4-fluorophenyl or3,4-difluorophenyl.
 4. A compound according to any one of claims 1 to 3in which R is CH₂OH or OCH₂CH₂OH.
 5. A compound according to claim 1which is:[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropylamino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;[1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;[1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;[1R-[1α,2α,3β(1R*,2*),5β]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;[1S-[1α,2α,3β,4α(1S*,R*)]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;[1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;[1S-[1α,2α3β5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;[1S-[1α,2α,3β(1S*,2R*),5]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol;or pharmaceutically acceptable salts or solvates thereof, or solvates ofsuch salts.
 6. A pharmaceutical composition comprising a compoundaccording to any one of claims 1 to 5 in combination with apharmaceutically acceptable diluent, adjuvent and/or carrier.
 7. Apharmaceutical composition comprising a compound according to any one ofclaims 1 to 5 for use in the treatment or prevention of myocardialinfarction, thrombotic stroke, transient ischaemic attacks, and/orperipheral vascular disease.
 8. A pharmaceutical composition comprisinga compound according to any one of claims 1 to 5 for use in thetreatment or prevention of unstable or stable angina.
 9. A compoundaccbrding to any one of claims 1 to 5 for use in therapy.
 10. A compoundaccording to any one of claims 1 to 5 for use in the treatment orprevention of myocardial infarction, thrombotic stroke, transientischaemic attacks, and/or peripheral vascular disease.
 11. A compoundaccording to any one of claims 1 to 5 for use in the treatment orprevention of unstable or stable angina.
 12. The use of a compoundaccording to any one of claims 1 to 5 as an active ingredient in themanufacture of a medicament for use in the treatment or prevention ofmyocardial infarction, thrombotic stroke, transient ischaemic attacks,and/or peripheral vascular disease.
 13. The use of a compound accordingto any one of claims 1 to 5 as an active ingredient in the manufactureof a medicament for use in the treatment or prevention of unstable orstable angina.
 14. A method of treatment or prevention of a plateletaggrecation disorder which comprises administering to a person sufferingfrom or susceptible to such a disorder a therapeutically effectiveamount of a compound according to any one of claims 1 to
 5. 15. A methodof treatment or prevention of myocardial infarction, thrombotic stroke,transient ischaemic attacks, and/or peripheral vascular disease, whichcomprises administering to a person suffering from or susceptible tosuch a condition a therapeutically effective amount of a compoundaccording to any one of claims 1 to
 5. 16. A method of treatment orprevention of unstable or stable angina which comprises administering toa person suffering from or susceptible to such a condition atherapeutically effective amount of a compound according to any one ofclaims 1 to
 5. 17. A process for the preparation of a compound offormula (I) which comprises reacting a compound of formula (II):

where R, R¹, R³ and R⁴ are as defined in claim 1, or are protectedderivatives thereof, or R³ and R⁴ together form a bond in the 5-memberedring, or R is CH₂CH₂OR where R is Cl ₆ alkyl or benzyl, and L is aleaving group, with a compound of formula (E):

where R² is defined in claim 1 or is a protected derivative thereof, inthe presence of a base in an inert solvent at ambient or elevatedtemperature, and optionally thereafter and in any order: converting oneor more functional groups into further functional groups; removing anyprotecting groups; forming, a pharmaceutically acceptable salt orsolvate, or a solvate of such a salt.
 18. The compounds:[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;[[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropy)lthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;[3aR-([3aα,4α,6α(1R*,2S*),6aα]-6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl4H-cyclopenta-1,3-dioxole-4-methanol;[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticacid, methyl ester;[3aR-(3aα,4α,6α,6aα)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]aceticacid, methyl ester;[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]aceticacid, methyl ester; [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[[7-[2-(3,4-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol;[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate;[3aR-(3aα,4α,6α,6aα)]-6-[7-Bromo-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate;[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[S-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,acetate;[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[3aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl4H-cyclopenta-1,3-dioxol-4-ol;[3 aR-[3aα,4α,6α,6aα(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;(1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]amino]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester; (1S-cis)2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticacid, ethyl ester; [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-aceticacid, ethyl ester; [1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-1-ethanol;[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol;[3aR-(3aα,4α,6α,6aα)]-2-[6-[7-Bromo-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol;[3aR-[3aα,4α,6aα(1R*,2S*),6aα]-2-[6-(7-Phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol;[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[[7-[(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-6-[[7-((3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[3aR-[3aα,4α,6aα(1R*,2S*),6aα]]-6-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;[3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicacid, phenylmethyl ester;[3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamicacid, phenylmethyl ester;[3aR-(3aα,4α,6α,6aα)]-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;2-(Butylthio)-4,6-dichloropyrimidine-5-amine;[3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-Amino-2-(butylthio)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol;[3a-R-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-2-[6-[[5-(Butylthio)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4yl]oxy]-ethanol.